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. 2009 Oct 31;1(1):35-42.
doi: 10.4254/wjh.v1.i1.35.

Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts

Yasuni Nakanuma  1 , Motoko Sasaki, Yasunori Sato, Xiangshan Ren, Hiroko Ikeda, Kenichi Harada
Affiliations

Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts

Yasuni Nakanuma et al. World J Hepatol. .

Abstract

Flat-type "biliary intraepithelial neoplasia (BilIN)" and papillary-type "intraductal papillary neoplasm of the bile duct (IPN-B)" are proposed as precursors of invasive, perihilar intrahepatic cholangiocarcinoma (ICC). Three carcinogenetic pathways are proposed: BilIN progressing to tubular adenocarcinoma, and IPN-B progressing to tubular adenocarcinoma or to colloid carcinoma. Carcinogenesis via BilIN was characterized by mucin core protein 2-/cytokeratin 20-(MUC2-/CK20-) with MUC1 expression, while carcinogenesis via IPN-B leading to tubular adenocarcinoma was associated with MUC1 expression or that to colloid carcinoma with MUC1-negativity. In both the BilIN and IPNB series, the expression of p21, p53, and cyclin D1 was upregulated with histological progression. Interestingly, p53 expression was upregulated at the invasive stage of BilIN, but was low in noninvasive BilIN, while p53 expression was upregulated in IPN-B1 and reached a plateau in IPN-B2 and invasive ICC. Expression of p16(INK4a), which was frequent in BilIN1, was decreased in BilIN-2/3 and invasive carcinoma. EZH2 expression showed a stepwise increase from BilIN to invasive carcinoma. Membranous expression of β-catenin and E-cadherin was more markedly decreased in ICC with BilIN than in ICC with IPNB. Interestingly, disruption of the membranous distribution of β-catenin and E-cadherin seems to result in the invasion and metastasis of carcinoma cells of BilIN and IPN-B expressing MMP-7 and MT1-MMP. Increased expression of cyclin D1 and c-myc was more frequent in the IPNB lineage than BilIN lineage, possibly related to the Wnt signaling pathway associated with the nuclear accumulation of β-catenin. In conclusion, BilIN and IPN-B progress to invasive ICC through characteristic multistep processes.

Keywords: Biliary intraepithelial neoplasm; Cytokeratin; Intraductal papillary neoplasm; Intrahepatic bile duct; Intrahepatic cholangiocarcinoma; Matrix metalloproteinase; Mucin; Polycomb group protein.

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Figures

Figure 1
Figure 1
Representative histological features of neoplasms (HE staining). A: BilIN-1; B: BilIN-2; BilIN-3; D: Invasive ICC; E: IPN-B. BilIN: biliary intraepithelial neoplasm; ICC: intrahepatic cholangiocarcinoma; IPN-B: intraductal papillary neoplasm of the bile duct[22].
Figure 2
Figure 2
During biliary multistep carcinogenesis, BilIN is proposed to progresses to conventional ICC (tubular adenocarcinoma), whereas IPN-B is associated with colloid carcinoma (mucinous carcinoma) or conventional ICC.
Figure 3
Figure 3
MUC1 is expressed in neoplastic cells of BilIN-3 (B) but not in those of BilIN1 (A) (Immunostaining). A: BilIN-1; B: BilIN-3.
Figure 4
Figure 4
Immunohistochemical expression of p16INK4a and EZH2 in BilIN-1 and BilIN-2. A: p16INK4a is intensely and frequently expressed in the cytoplasm and nuclei in BilIN-1 (left), but such expression is unclear in BilIN-2 (right); B: While EZH2 is occasionally expressed in the nuclei in BilIN-1 (left), this expression increases markedly in BilIN-2 (right)[22].
Figure 5
Figure 5
Semiquantitative evaluation of P16INK4a and EZH2 in BilIN-1, -2, and -3, and invasive cholangiocarcinoma (CC). The labeling index (LI) reflects the percentage of cells immunohistochemically positive for P16INK4a or EZH2 in each lesion of BilIN-1, -2, and -3, and invasive CC. bP < 0.01 vs BilIN-1. A: The LI of P16INK4a expression (mean ± SD) decreases with the progressing of BilINs and is higher in invasive CC; B: Expression of EZH2 increases with the progression of BilINs and is greater in invasive CC[22].
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